MAIDS is a retrovirus-induced immunodeficiency syndrome of mice characterized by progressive lymphoproliferation and immunodeficiency. The disease is dependent on expression in genetically susceptible mice of an unusual Gag protein encoded by a murine leukemia virus. Induction and progression of disease are dependent on interactions of T cells and B cells with B cells being the primary target of infection. The current studies are focused on the characteristics of B cells needed to induce disease. For this pupose, we studied mice deficient in expression of signaling molecules that facilitate (CD19, Vav) or inhibit (CD22) normal B cell activation. These studies showed that CD19 and Vav-deficient mice were markedly impaired in development of MAIDS due to decreased replication of the causative virus. In contrast, CD22-deficient mice exhibited increased sensitivity. B cells are not thus passive vessels for expression of the MAIDS defective virus, but require activation for participation in disease.